Iminopyrimidine NMDA NR2B receptor antagonists

ABSTRACT

Compounds described by the chemical structural formula                    
     or a pharmaceutically acceptable salt thereof, are useful in the treatment of pain, migraine, depression, anxiety, schizophrenia, Parkinson&#39;s disease, stroke, and in the treatment of neuropathies including postherpetic neuralgia, central pain from spinal cord injury, and phantom limb pain.

This application claims priority from provisional application Ser. No.60/214,654, filed Jun. 26, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel iminopyrimidine compounds. Inparticular, this invention relates to novel iminopyrimidine compoundseffective as NMDA NR2B antagonists.

2. Related Background

Ions play a key role in processes related to chronic pain andpain-associated neurotoxicity—primarily by acting throughN-methyl-D-aspartate (“NMDA”) receptors. Thus, inhibition of suchaction—by employing ion channel antagonists, particularly NMDAantagonists—can be beneficial in the treatment and control of pain.

Known NMDA antagonists include ketamine, dextromophan, and3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (“CPP”). Althoughthese compounds have been reported (J. D. Kristensen, et al., Pain,51:249-253 (1992); K. Eide, et al., Pain, 61:221-228 (1995); D. J. Knox,et al., Anaesth. Intensive Care 23:620-622 (1995); and M. B. Max, etal., Clin. Neuropharmacol. 18:360-368 (1995)) to produce symptomaticrelief in a number of neuropathies including postherpetic neuralgia,central pain from spinal cord injury, and phantom limb pain, widespreaduse of these compounds is precluded by their undesirable side effects.Such side effects at analgesic doses include psychotomimetic effectssuch as dizziness, headache, hallucinations, dysphoria, and disturbancesof cognitive and motor function. Additionally, more severehallucinations, sedation, and ataxia are produced at doses onlymarginally higher than analgesic doses. Thus, it would be desirable toprovide novel NMDA antagonists that are absent of undesirable sideeffects or that produce fewer and/or milder side effects.

NMDA receptors are heteromeric assemblies of subunits, of which twomajor subunit families designated NR1 and NR2 have been cloned. Withoutbeing bound by theory, it is generally believed that the variousfunctional NMDA receptors in the mammalian central nervous system(“CNS”) are only formed by combinations of NR1 and NR2 subunits, whichrespectively express glycine and glutamate recognition sites. The NR2subunit family is in turn divided into four individual subunit types:NR2A, NR2B, NR2C, and NR2D. L. Ishii, et al., J. Biol. Chem.,268:2836-2843 (1993), A. Wenel, et al., Neural Report, 7:45-48 (1995),and D. J. Laurie et al., Mol. Brain Res., 51:23-32 (1997) describe howthe various resulting combinations produce a variety of NMDA receptorsdiffering in physiological and pharmacological properties such as iongating properties, magnesium sensitivity, pharmacological profile, aswell as in anatomical distribution.

For example, while NR1 is found throughout the brain, NR2 subunits aredifferentially distributed. In particular, it is believed that thedistribution map for NR2B lowers the probability of side effects whileproducing pain relief. S. Boyce, et al., Neuropharmacology, 33:1609-1611(1994) describes the regional distribution of the NMDA receptorcontining the NR2B subunit protein in rat lumbar spinal cord. Thus, itwould be desirable to provide novel NMDA antagonists that target theNR2B receptor.

SUMMARY OF THE INVENTION

Compounds described by the following chemical structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein

i) Ar is an aromatic group, the aromatic group being phenyl, naphthyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl,quinoxalinyl, furyl, thienyl, pyrrolyl, benzimidazolyl, indolyl,quinolinyl, isoquinolinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, imidazolyl, benzthienyl, or benzofuryl, the aromatic groupoptionally substituted by one or two substituents, each substituentindependently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

ii) R₁ is a phenyl; or —CH₂—, —NH—, —NR₄—, —NR₅—, or ═N— when optionallyconnected either via B₁ to R₂ or via B₂ to R₃;

iii) R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, whereinthe groups optionally may be substituted by one or two substituents,each substituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;R₂ optionally is —CH₂— or ═CH— connected via B₁ to R₁;

iv) R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, whereinthe groups optionally may be substituted by one or two substituents,each substituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;R₃ optionally is —CH₂— or ═CH— connected via B₂ to R₁;

v) R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

vi) R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, whereinthe groups optionally may be substituted by one or two substituents,each substituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

vii) R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

viii) R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

ix) B₁ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—, or absent; and

x) B₂ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—, or absent;

are useful in the treatment of pain, migraine, depression, anxiety,schizophrenia, Parkinson's disease, stroke, and in the treatment ofneuropathies including postherpetic neuralgia, central pain from spinalcord injury, and phantom limb pain.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are described by the followingchemical structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein

i) Ar is an aromatic group, the aromatic group being phenyl, naphthyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl,quinoxalinyl, furyl, thienyl, pyrrolyl, benzimidazolyl, indolyl,quinolinyl, isoquinolinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, imidazolyl, benzthienyl, or benzofuryl, the aromatic groupoptionally substituted by one or two substituents, each substituentindependently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

ii) R₁ is a phenyl; or —CH₂—, —NH—, —NR₄—, —NR₅—, or ═N— when optionallyconnected either via B₁ to R₂ or via B₂ to R₃;

iii) R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, whereinthe groups optionally may be substituted by one or two substituents,each substituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;R₂ optionally is —CH₂— or ═CH— connected via B₁ to R₁;

iv) R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, whereinthe groups optionally may be substituted by one or two substituents,each substituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;R₃ optionally is —CH₂— or ═CH— connected via B₂ to R₁;

v) R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

vi) R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, whereinthe groups optionally may be substituted by one or two substituents,each substituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

vii) R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

viii) R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

ix) B₁ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—, or absent; and

x) B₂ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—, or absent.

In an aspect, the compounds of this invention are described by formula(I), or a pharmaceutically acceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is a phenyl; or R₁ is —CH₂—, —NH—, —NR₄—, —NR₅—, or ═N— whenoptionally connected either via B₁ to R₂ or via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl; R₂optionally is —CH₂— or —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl; R₃optionally is —CH₂— or —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—, or absent; and

B₂ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—, or absent.

In one aspect, the compounds of the present invention are described byformula (I), or a pharmaceutically acceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is a phenyl;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is absent;

R₅ is absent;

R₆ is absent;

R₇ is absent;

B₁ is absent; and

B₂ is absent.

In one embodiment of this aspect, the compounds of the present inventionare described by formula (I), or a pharmaceutically acceptable saltthereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is a phenyl;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, wherein the groupsoptionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is absent;

R₄ is absent;

R₅ is absent;

R₆ is absent;

R₇ is absent;

B₁ is absent; and

B₂ is absent.

In another embodiment of this aspect, the compounds of the presentinvention are described by formula (I), or a pharmaceutically acceptablesalt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is a phenyl;

R₂ is absent;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is absent;

R₅ is absent;

R₆ is absent;

R₇ is absent;

B₁ is absent; and

B₂ is absent.

In a second aspect, the compounds of the present invention are describedby formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₁ to R₂;

R₂ is —CH₂— or —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—; and

B₂ is absent.

In an embodiment of the second aspect, the compounds of the presentinvention are described by formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent; and

B₁ is —CH₂—.

In another embodiment of the second aspect, the compounds of the presentinvention are described by formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent; and

B₁ is —CH₂CH₂—.

In still another embodiment of the second aspect, the compounds of thepresent invention are described by formula (I) or a pharmaceuticallyacceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent; and

B₁ is —CH═CH—.

In another embodiment of the second aspect, the compounds of the presentinvention are described by formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₁ to R₂;

R₂ is —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent; and

B₁ is ═CH—.

In a third aspect of the invention, the compounds of the presentinvention are described by formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— or —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂—, ═CH—, —CH₂CH₂—, —CH═CH—.

In an embodiment of the third aspect of the invention, the compounds ofthe present invention are described by formula (I) or a pharmaceuticallyacceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂—.

In another embodiment of the third aspect of the invention, thecompounds of the present invention are described by formula (I) or apharmaceutically acceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂CH₂—.

In still another embodiment of the third aspect of the invention, thecompounds of the present invention are described by formula (I) or apharmaceutically acceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH═CH—.

In another embodiment of the third aspect of the invention, thecompounds of the present invention are described by formula (I) or apharmaceutically acceptable salt thereof, wherein

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —CH₂— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is ═CH—.

In a fourth aspect of the invention, the compounds of the invention arerepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₁ to R₂;

R₂ is —CH₂— or —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂—, ═CH—, —CH₂CH₂—, or —CH═CH— and

B₂ is absent.

In an embodiment of the fourth aspect of the invention, the compounds ofthe invention are represented by formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂—, and

B₂ is absent.

In yet another embodiment of the fourth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂CH₂—; and

B₂ is absent.

In still another embodiment of the fourth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH═CH— and

B₂ is absent.

In an embodiment of the fourth aspect of the invention, the compounds ofthe invention are represented by formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₁ to R₂;

R₂ is —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is ═CH—; and

B₂ is absent.

In a fifth aspect of the invention, the compounds of the invention arerepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— or —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂—, ═CH—, —CH₂CH₂—, or —CH═CH—.

In an embodiment of the fifth aspect of the invention, the compounds ofthe invention are represented by formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂—.

In yet another embodiment of the fifth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂is ═CH—.

In still another embodiment of the fifth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂CH₂—.

In another embodiment of the fifth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is —NH—, —NR₄—, or —NR₅— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH═CH—.

In a sixth aspect of the invention, the compounds of the invention arerepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₁ to R₂;

R₂ is —CH₂— or —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂—, ═CH—, —CH₂CH₂—, or —CH═CH— and

B₂ is absent.

In an embodiment of the sixth aspect of the invention, the compounds ofthe invention are represented by formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂— and

B₂ is absent.

In yet another embodiment of the sixth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH₂CH₂— and

B₂ is absent.

In still another embodiment of the sixth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₁ to R₂;

R₂ is —CH═ connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is ═CH—, and

B₂ is absent.

In another embodiment of the sixth aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₁ to R₂;

R₂ is —CH₂— connected via B₁ to R₁;

R₃ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is —CH═CH— and

B₂ is absent.

In a seventh aspect of the invention, the compounds of the invention arerepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— or —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂—, ═CH—, —CH₂CH₂—, or —CH═CH—.

In an embodiment of the seventh aspect of the invention, the compoundsof the invention are represented by formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂—.

In still another embodiment of the seventh aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH═ connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is ═CH—.

In yet another embodiment of the seventh aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH₂CH₂—.

In still another embodiment of the seventh aspect of the invention, thecompounds of the invention are represented by formula (I), or apharmaceutically acceptable salt thereof, wherein:

Ar is a phenyl ring, optionally substituted by one or two substituents,each substituent independently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₁ is ═N— connected via B₂ to R₃;

R₂ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₃ is —CH₂— connected via B₂ to R₁;

R₄ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₅ is a phenyl group, a C₁₋₄alkylphenyl group, or absent, wherein thegroups optionally may be substituted by one or two substituents, eachsubstituent is independently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl;

R₆ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

R₇ is a phenyl group, a C₁₋₄alkylphenyl group, or absent;

B₁ is absent; and

B₂ is —CH═CH—.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “aryl group” includes single and fused multiple aromatic rings.Heteroatoms can optionally be included in the rings. Examples of arylgroups are phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, imidazolyl, quinoxalinyl, furyl, thienyl, pyrrolyl,benzimidazolyl, indolyl, quinolinyl, isoquinolinyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, benzthienyl, andbenzofuryl.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of pain, migraine, depression,anxiety, schizophrenia, Parkinson's disease, stroke, and in thetreatment of neurophathic conditions such as postherpetic neuralgia,central pain from spinal cord injury, and phantom limb pain which areresponsive to NOVA NR2B inhibition, or alternatively about 0.5 mg toabout 7 g per patient per day. For example, inflammation may beeffectively treated by the administration of from about 0.01 mg to 50 mgof the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day. Further, it isunderstood that the NR2B antagonist compounds of this invention can beadministered at prophylactically effective dosage levels to prevent theabove-recited conditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as NR2B antagonists.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, pain, migraine, depression, anxiety, schizophrenia,Parkinson's disease, stroke, and neurophathic conditions such aspostherpetic neuralgia, central pain from spinal cord injury, andphantom limb pain—maladies that are amenable to amelioration throughNMDA NR2B inhibition—by the administration of an effective amount of thecompounds of this invention. The term “mammals” includes humans, as wellas other animals such as, for example, dogs, cats, horses, pigs, andcattle. Accordingly, it is understood that the treatment of mammalsother than humans is the treatment of clinical correlating afflictionsto those above recited examples that are human afflictions.

EXAMPLES

The following Examples 1-29 are shown as trifluoroacetic acid (“TFA”)salts. The trifluoroacetic acid salt form arose from the HPLC procedureand not because the salt per se was desired. The free bases of thetrifluoroacetic acid salts can be readily obtained by the followingprocedure. Dissolve the salt in a 1:1 mixture of ethyl acetate andsaturated aqueous sodium bicarbonate, separate the layers, dry theorganic part over Na₂SO₄ and concentrate. The resulting residue is thebase of the starting trifluoroacetic acid salt.

Example 1

Example 1 was prepared by the following method, Procedure A: A solutionof 2-iminopiperidine (60 mg, 0.61 mmol) was dissolved in 5% MeCN/THF (5mL) at room temperature. 3-Phenyl-2-propynenitrile (77 mg, 0.61 mmol)was added in one portion and the resulting reaction mixture was stirred2 h. The reaction mixture was poured into ethyl acetate and aqueousNaHCO₃. The layers were separated. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified bypreparative reverse phase HPLC to give Example 1 (134 mg, 65% yield as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 9.42 (br s, 1H), 7.58-7.50 (m,3H), 7.38-7.35 (m 2H), 6.81 (s 1H), 6.73 (br s, 1H), 3.84 (t, J=5.8 Hz,2H), 3.10 (t, J=6.6 Hz, 2H), 2.03-1.94 (m, 4H) ppm; ¹³C NMR (125 MHz),CDCl₃) δ 163.5, 163.0, 157.4, 131.5, 130.6, 129.5, 128.3, 106.6, 50.3,31.5, 21.8, 18.1, ppm; high resolution mass spectrum m/z 226.1353[(M+H)⁺; calc'd for C₁₄H₁₆N₃: 226.1339].

Example 2

Example 2 was prepared by the following method, Procedure B: A solutionof 2-iminopiperidine (60 mg, 0.61 mmol) was dissolved in 5% MeCN/THF (5mL) at room temperature. NaHMDS (1.0M/THF, 1.22 mL. 1.22 mmol) was addeddropwise and the resulting solution was stirred at room temperature for5 min. 3-Phenyl-2-propynenitrile (77 mg, 0.61 mmol) was then added inone portion, the reaction mixture turned dark red and was stirred for 5min. The reaction mixture was poured onto ethyl acetate and aqueousNaHCO₃ and the layers separated. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified bypreparative reverse HPLC to give Example 2 (107 mg, 52% yield) as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 9.74 (br s, 1H), 9.18 (br s, 1H),8.04 (dd, J=7.8, 1.5 Hz, 2H), 7.56-7.43 (m, 4H), 4.10 (t, J=6.2 Hz, 2H),3.13 (t, J=6.5 Hz, 2H), 2.18-2.11 (m, 2H), 2.02-1.98 (m, 2H) ppm; ¹³CNMR (125 MHz), CDCl₃) δ 161.2, 158.3, 157.7, 132.2, 129.1, 129.0, 127.5,101.4, 47.0, 32.3, 21.4, 18.1, ppm; high resolution mass spectrum m/z226.1351 [(M+H)⁺; calc'd for C₁₄H₁₆N₃: 226.1339].

Example 3

Example 3 was prepared by following procedure A except using4-phenyl-pyrrolidin-2-ylidene instead of 2-iminopiperidine. (61% yield):¹H NMR (500 MHz, CDCl₃) δ 10.39 (br s, 1H), 9.63 (br s, 1H), 7.51-7.46(m, 5H), 7.36-7.28 (m, 3H); 7.24 (, 2H), 7.04 (s, 1H); 4.48 (dd, 1H),4.25 (dd, 1H), 3.90 (quint, 1H), 3.58 (dd, 1H), 3.48 (dd, 1H) ppm; ¹³CNMR (125 MHz), CDCl₃) δ 166.8, 165.5, 154.2, 138.1, 131.8, 130.2, 129.5,129.4, 128.3, 128.2, 127.0, 104.9, 59.0, 39.7, 39.5 ppm; mass spectrumm/z 288 [(M+H)⁺; calc'd for C₁₉H₁₈N₃: 288].

Example 4

Example 4 was prepared by following procedure B except using4-phenyl-pyrrolidin-2-ylidene instead of 2-iminopiperidine. (63% yield):¹H NMR (500 MHz, CDCl₃) δ 10.02 (br s, 1H), 9.67 (br s, 1H), 8.07 (d,2H), 7.61-7.49 (m, 4H), 7.38-7.32 (m, 3H), 7.24 (m, 2H), 4.97 (dd, 1H),4.35 (dd, 1H), 4.01 (quint, 1H), 3.66 (dd, 1H), 3.41 (dd, 1H) ppm; ¹³CNMR (125 MHz), CDCl₃) δ 163.3, 162.4, 155.8, 138.6, 134.4, 132.3, 129.4,129.2, 128.2, 127.8, 126.8, 101.8, 55.8, 39.3, 38.5 ppm; mass spectrumm/z 288 [(M+H)⁺; calc'd for C₁₉H₁₈N₃: 288].

Example 5

Example 5 was prepared by following procedure A except usingN-phenyl-benzamidine instead of 2-iminopiperidine. (25% yield): massspectrum m/z 324 [(M+H)⁺; calc'd for C₂₂H₁₈N₃: 324].

Example 6

Example 6 was prepared by following procedure B exceptN-phenyl-benzamidine instead of 2-iminopiperidine. (31% yield): massspectrum m/z 324 [(M+H)⁺; calc'd for C₂₂H₁₈N₃: 324].

Example 7

Example 7 was prepared by following procedure A except usingN-(3,4-dichloro-phenyl)-benzamidine instead of 2-iminopiperidine. (5%yield): mass spectrum m/z 393 [(M+H)⁺; calc'd for C₂₂H₁₆Cl₂N₃: 393].

Example 8

Example 8 was prepared by following procedure B except usingN-(3,4-dichloro-phenyl)-benzamidine instead of 2-iminopiperidine. (32%yield): mass spectrum m/z 393 [(M+H)⁺; calc'd for C₂₂H₁₆Cl₂N₃: 393].

Example 9

Example 9 was prepared by following procedure A except using3-(4-chloro-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (52% yield): ¹H NMR (300 MHz, CD₃OD) δ 7.61(d, 2H), 7.53 (d, 2H), 6.57 (s 1H), 3.81 (t, 2H), 3.10 (t, 2H), 1.95 (m,4H) ppm; mass spectrum m/z 260 [(M+H)⁺; calc'd for C₁₄H₁₅ClN₃: 260].

Example 10 L-452493-001X

Example 10 was prepared by following procedure B except using3-(4-chloro-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (61% yield): ¹H NMR (300 MHz, CD₃OD) δ 8.13(d, 2H), 7.55 (d, 2H), 7.30 (s, 1H), 3.99 (t, 2H), 3.20 (t, 2H), 2.18(m, 2H), 2.01 (m, 2H) ppm; mass spectrum m/z 260 [(M+H)⁺; calc'd forC₁₄H₁₅ClN₃: 260].

Example 11 L-453449-001G

Example 11 was prepared by following procedure A except using3-(4-methoxy-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (60% yield): ¹H NMR (300 MHz, CD₃OD) δ 7.44(d, 2H), 7.12 (d, 2H), 6.57 (s 1H), 3.90 (t, 2H), 3.86 (s, 3H), 3.10 (t,2H), 1.97 (m, 4H) ppm; mass spectrum m/z 256 [(M+H)⁺; calc'd forC₁₅H₁₈N_(3O): 256].

Example 12

Example 12 was prepared by following procedure B except using3-(4-methoxy-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (55% yield): ¹H NMR (300 MHz, CD₃OD) δ 8.10(d, 2H), 7.19 (s, 1H), 7.05 (d, 2H), 3.97 (t, 2H), 3.89 (s, 3H), 3.17(t, 2H), 2.18 (m, 2H), 2.00 (m, 2H) ppm; mass spectrum m/z 256 [(M+H)⁺;calc'd for C₁₅H₁₈N_(3O): 256].

Example 13

Example 13 was prepared by following procedure A except using3-(4-methyl-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (56% yield): ¹H NMR (300 MHz, CD₃OD) δ 7.40(m, 4H), 6.57 (s 1H), 3.85 (t, 2H), 3.10 (t, 2H), 2.41 (s, 3H), 1.96 (m,4H) ppm; mass spectrum m/z 240 [(M+H)⁺; calc'd for C₁₅H₁₈N₃: 240].

Example 14

Example 14 was prepared by following procedure B except using3-(4-methyl-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (58% yield): ¹H NMR (300 MHz, CD₃OD) δ 8.01(d, 2H), 7.35 (d, 2H), 7.22 (s, 1H), 3.98 (t, 2H), 3.18 (t, 2H), 2.18(m, 2H), 2.00 (m, 2H) ppm; mass spectrum m/z 240 [(M+H)⁺; calc'd forC₁₅H₁₈N₃: 240].

Example 15

Example 15 was prepared by following procedure A except using3-(2-chloro-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (15% yield): ¹H NMR (300 MHz, CD₃OD) δ7.78-7.44 (m, 4H), 6.58 (s 1H), 3.77 (m, 2H), 3.12 (m, 2H), 1.98 (m, 4H)ppm; mass spectrum m/z 260 [(M+H)⁺; calc'd for C₁₄H₁₅ClN₃: 260].

Example 16

Example 16 was prepared by following procedure B except using3-(2-chloro-phenyl)-2-propynenitrile instead of3-phenyl-2-propynenitrile. (48% yield): ¹H NMR (300 MHz, CD₃OD) δ 7.77(d, 1H), 7.60-7.43 (m, 3H), 7.28 (s, 1H), 4.02 (t, 2H), 3.18 (t, 2H),2.20 (m, 2H), 2.03 (m, 2H) ppm; mass spectrum m/z 260 [(M+H)⁺; calc'dfor C₁₄H₁₅ClN₃: 260].

Example 17

Example 17 was prepared by the following procedure. A solution of4,5-diphenyl-imidazolidin-2-ylideneamine hydrobromide (50 mg, 0.16 mmol)was dissolved in ethyl acteate and washed with aqueous NaHCO3. Theorganic layer was dried over MgSO4, filtered and concentrated. Theresidue was then dissolved in EtOH (1 mL) at room temperature.3-Phenyl-2-propynenitrile (25 mg, 0.19 mmol) was added in one portionand the resulting reaction mixture was heated to 90 C. and stirred for15 h. The reaction mixture was concentrated and the residue was purifiedby preparative reverse phase HPLC to give Example 17: ¹H NMR (300 MHz,CDCl₃) δ 9.50 (s, 1H), 9.35 (s, 1H), 9.07 (s, 1H), 7.40-6.90 (m, 13H),6.37 (d, 2H), 6.21 (s, 1H), 5.77 (d, 2H), 5.56 (d, 2H) ppm; massspectrum m/z 365 [(M+H)⁺; calc'd for C₂₄H₂₁N₄: 365].

Example 18 L-425037-001E

Example 18 was prepared by the following procedure. A solution of1-benzyl-imidazolidin-2-ylideneamine (35 mg, 0.2 mmol) was dissolved inMeCN (2 mL) at room temperature. 3-Phenyl-2-propynenitrile (25 mg, 0.2mmol) was added in one portion and the resulting reaction mixture wasstirred for 1 h. The reaction mixture was poured into ethyl acetate andaqueous K₂CO₃. The layers were separated. The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified bypreparative reverse phase HPLC. Two products were isolated (Example 17and Example 18). Example 18 is the major product: ¹H NMR (300 MHz,CDCl₃) δ 7.60-7.28 (m, 10H), 6.40 (s, 1H), 4.66 (s, 2H), 4.11 (t, 2H),3.69 (t, 2H) ppm; mass spectrum m/z 303 [(M+H)⁺; calc'd for C₁₉H₁₉N₄:303].

Example 19 L-425038-001N

Example 19 was prepared by following the procedure given in Example 18.Example 19 was the minor product is the above reaction: ¹H NMR (300 MHz,CDCl₃) δ 8.05 (d, 2H), 7.58-7.30 (m, 8H), 6.62 (s, 1H), 4.78 (s, 2H),4.24 (m, 2H), 3.82 (m, 2H) ppm; mass spectrum m/z 303 [(M+H)⁺; calc'dfor C₁₉H₁₉N₄: 303].

Example 20 L-425649-001Y

Example 20 was prepared by the following procedure. A solution of(3-chloro-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine (25 mg, 0.12mmol) was dissolved in MeCN (2 mL) at room temperature.3-Phenyl-2-propynenitrile (15 mg, 0.12 mmol) was added in one portionand the resulting reaction mixture was stirred for 15 h. The reactionmixture was concentrated and purified by preparative reverse phase HPLCto give example 20: ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.27 (m, 8H), 5.89(s, 1H), 5.27 (s, 2H), 4.20-4.00 (m, 4H) ppm; mass spectrum m/z 337[(M+H)⁺; calc'd for C₁₉H₁₈ClN₄: 337].

Example 21 L-425652-001E

Example 21 was prepared by following the procedure for Example 20 exceptusing (2-methoxy-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine instead of(3-chloro-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine: mass spectrumm/z 333 [(M+H)⁺; calc'd for C₂₀H₂₁N_(4O): 333].

Example 22 L-425653-001N

Example 22 was prepared by following the procedure for Example 20 exceptusing (3-methoxy-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine instead of(3-chloro-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine: mass spectrumm/z 333 [(M+H)⁺; calc'd for C₂₀H₂₁N_(4O): 333].

Example 23 L-425654-001X

Example 23 was prepared by following the procedure for Example 20 exceptusing (3,5-dichloro-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine insteadof (3-chloro-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine: mass spectrumm/z 371 [(M+H)⁺; calc'd for C₁₉H_(17Cl2)N₄: 371].

Example 24 L-425656-001P

Example 24 was prepared by following the procedure for Example 20 exceptusing (3,5-dimethyl-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine insteadof (3-chloro-benzyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine: mass spectrumm/z 331 [(M+H)⁺; calc'd for C₂₁H₂₃N₄: 331].

Example 25 L426021-001E

Example 25 was prepared by the following procedure. A solution of5-phenyl-8H-imidazo[1,2-a]pyrimidin-7-ylideneamine (10 mg, 0.05 mmol)was dissolved in xylene (2 mL) at room temperature. 3,5-Dimethyl benzylbromide (10 mg, 0.05 mmol) was added in one portion and the resultingreaction mixture was heated to 140 C. and stirred for 1 h. The reactionmixture was concentrated and purified by preparative reverse phase HPLCto give example 25: ¹H NMR (300 MHz, CDCl₃) δ 9.39 (br s, 1H), 7.60 (s,5H), 7.24 (s, 1H), 7.19 (s, 1H), 7.08 (m, 2H), 6.95 (s, 2H), 6.25 (br s,1H), 5.21 (s, 2H), 2.35 (s, 6H) ppm; mass spectrum m/z 329 [(M+H)⁺;calc'd for C₂₁H₂₁N₄: 329].

Example 26 L-426022-001N

Example 26 was prepared by following the procedure for Example 25 exceptusing benzyl bromide instead of 3,5-dimethyl benzyl bromide: massspectrum m/z 301 [(M+H)⁺; calc'd for C₁₉H₁₇N₄: 301].

Example 27 L-426023-001X

Example 27 was prepared by following the procedure for Example 25 exceptusing phenethyl bromide instead of 3,5-dimethyl benzyl bromide: massspectrum m/z 315 [(M+H)⁺; calc'd for C₂₀H₁₉N₄: 315].

Example 28 L-426666-001B

Example 28 was prepared by the following procedure. A solution of1-(3,5-dichloro-benzyl)-imidazolidin-2-ylideneamine (30 mg, 0.12 mmol)was dissolved in MeCN (3 mL) at room temperature.3-Phenyl-2-propynenitrile (15 mg, 0.12 mmol) was added in one portionand the resulting reaction mixture was stirred for 1 h. The reactionmixture was concentrated and purified by preparative reverse phase HPLCto give Example 28: ¹H NMR (300 MHz, CDCl₃) δ 8.65 (br s, 1H), 8.00 (d,2H), 7.55-7.42 (m, 3H), 7.25 (m, 3H), 6.78 (s, 1H), 6.30 (br s, 1H),4.66 (s, 2H), 4.45 (t, 2H), 3.80 (t, 2H) ppm; mass spectrum m/z 372[(M+H)⁺; calc'd for C₁₉H_(17Cl2)N₄: 372].

Example 29 L-429067-001K

Example 29 was prepared by the following procedure. A solution of5-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-7-ylideneamine (12 mg,0.05 mmol) was dissolved in xylene (2 mL) at room temperature.3,5-Dimethyl benzyl bromide (10 mg, 0.05 mmol) was added in one portionand the resulting reaction mixture was heated to 140 C. and stirred for1 h. The reaction mixture was concentrated and purified by preparativereverse phase HPLC to give example 29: ¹H NMR (300 MHz, CDCl₃) δ 7.59(s, 5H), 7.00 (s, 3H), 6.05 (s, 1H), 4.65 (s, 2H), 4.18 (dd, 2H), 3.70(dd, 2H), 2.32 (s, 6H) ppm; mass spectrum m/z 331 [(M+H)⁺; calc'd forC₂₁H₂₃N₄: 331].

Examples 30-58 are prepared by forming the free base compound from theabove Examples 1-29:

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

Example 41

Example 42

Example 43

Example 44

Example 45

Example 46

Example 47

Example 48

Example 49

Example 50

Example 51

Example 52

Example 53

Example 54

Example 55

Example 56

Example 57

Example 58

What is claimed is:
 1. A compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein Ar is an aromaticgroup, said aromatic group being phenyl, naphthyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, quinoxalinyl, furyl,thienyl, pyrrolyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl,benzthienyl, or benzofuryl, said aromatic group optionally substitutedby one or two substituents, each substituent independently is halogen,C₁₋₄alkyl, or oxyC₁₋₄alkyl; R₁ is a phenyl; R₂ is a phenyl group, aC₁₋₄alkylphenyl group, or absent, wherein the groups optionally may besubstituted by one or two substituents, each substituent isindependently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl; and R₃ is a phenylgroup, a C₁₋₄alkylphenyl group, or absent, wherein the groups optionallymay be substituted by one or two substituents, each substituent isindependently halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein: Ar is a phenyl ring, optionally substituted by one or twosubstituents, each substituent independently is halogen, C₁₋₄alkyl, oroxyC₁₋₄alkyl.
 3. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: Ar is a phenyl ring,optionally substituted by one or two substituents, each substituentindependently is halogen, C₁₋₄alkyl, or oxyC₁₋₄alkyl.
 4. The compoundaccording to claim 3, or a pharmaceutically acceptable salt thereof,wherein: R₃ is absent.
 5. The compound according to claim 3, or apharmaceutically acceptable salt thereof, wherein R₂ is absent.
 6. Acompound represented by:

or a pharmaceutically acceptable salt thereof.
 7. A compound representedby


8. A method of treatment of Parkinson's disease comprising the step ofadministering a therapeutically effective amount of a compund accordingto claim 1, or a pharmaceutically acceptable salt thereof.